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l -Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm
Abstract
Background— l -Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. l -Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of l -arginine on vascular reactivity and functional capacity in patients with PAD. Methods and Results— The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral l -arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. l -Arginine supplementation significantly increased plasma l -arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both l -arginine- and placebo-treated patients, the improvement in the l -arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P =0.024). Conclusions— In patients with PAD, long-term administration of l -arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the l -arginine-treated group. As opposed to its short-term administration, long-term administration of l -arginine is not useful in patients with intermittent claudication and PAD.
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“Soon after its discovery in cells and tissue, ADMA was recognized as an important marker for cardiovascular disease progression (656, 829, 961, 1011, 1053, 1068).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1011]
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Cites
Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries
Ludmer, P. L., Selwyn, A. P., Shook, T., Wayne, R. R., Mudge, G. H., Alexander, R. W., & Ganz, P. (1986) · New England Journal of Medicine · doi:10.1056/nejm198610233151702 · Cited by 2,422
Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure
Leone, A., Moncada, S., Vallance, P., Calver, A., & Collier, J. (1992) · The Lancet · doi:10.1016/0140-6736(92)90865-z · Cited by 2,107
Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.
Murohara, T., Asahara, T., Silver, M., Bauters, C., Masuda, H., Kalka, C., Kearney, M., Chen, D., Symes, J. F., Fishman, M. C., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1560 · Cited by 1,186
Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans.
Creager, M. A., Cooke, J. P., Mendelsohn, M. E., Gallagher, S. J., Coleman, S. M., Loscalzo, J., & Dzau, V. J. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114688 · Cited by 1,017
Self-citationDrexler, H., Zeiher, A. M., Meinzer, K., & Just, H. (1991) · The Lancet · doi:10.1016/0140-6736(91)92372-9 · Cited by 794
NITRIC OXIDE SYNTHASE: Role in the Genesis of Vascular Disease
Cooke, J. P., & Dzau, V. J. (1997) · Annual Review of Medicine · doi:10.1146/annurev.med.48.1.489 · Cited by 706
Self-citationAntiatherogenic effects of L-arginine in the hypercholesterolemic rabbit.
Cooke, J. P., Singer, A. H., Tsao, P. S., Zera, P. H., Rowan, R. A., & Billingham, M. E. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115937 · Cited by 683
Self-citationHomocysteine Impairs the Nitric Oxide Synthase Pathway
Stuehlinger, M., Tsao, P. S., Her, J. H., Kimoto, M., Balint, R. F., & Cooke, J. P. (2001) · Circulation · doi:10.1161/hc4601.098514 · Cited by 662
Self-citationImpaired Nitric Oxide Synthase Pathway in Diabetes Mellitus
Lin, K. Y., Ito, A., Asagami, T., Tsao, P. S., Adimoolam, S., Kimoto, M., Tsuji, H., Reaven, G. M., & Cooke, J. P. (2002) · Circulation · doi:10.1161/01.cir.0000027109.14149.67 · Cited by 651
Self-citationNovel Mechanism for Endothelial Dysfunction
Ito, A., Tsao, P. S., Adimoolam, S., Kimoto, M., Ogawa, T., & Cooke, J. P. (1999) · Circulation · doi:10.1161/01.cir.99.24.3092 · Cited by 629
Self-citationMoncada, S., Rees, D. D., Schulz, R., & Palmer, R. M. J. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.6.2166 · Cited by 489
Nitric oxide and atherosclerosis: An update
Claudio Napoli, A., de Nigris, F., Williams‐Ignarro, S., Pignalosa, O., Sica, V., & Ignarro, L. J. (2006) · Nitric Oxide · doi:10.1016/j.niox.2006.03.011 · Cited by 471
Kielstein, J. T., Impraim, B., Simmel, S., Bode‐Böger, S. M., Tsikas, D., Frölich, J. C., Hoeper, M. M., Haller, H. G., & Fliser, D. (2003) · Circulation · doi:10.1161/01.cir.0000105764.22626.b1 · Cited by 400
Asymmetrical Dimethylarginine: The Über Marker?
Cooke, J. P. (2004) · Circulation · doi:10.1161/01.cir.0000126823.07732.d5 · Cited by 396
Self-citationRegulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase
MacAllister, R. J., Parry, H., Kimoto, M., Ogawa, T., Russell, R. J., Hodson, H. F., Whitley, G. S. J., & Vallance, P. J. (1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb16069.x · Cited by 394
Schulman, S. P., Becker, L. C., Kass, D. A., Champion, H. C., Terrin, M. L., Forman, S., Ernst, K. V., Kelemen, M. D., Townsend, S. N., Capriotti, A., et al. (2006) · JAMA · doi:10.1001/jama.295.1.58 · Cited by 357
Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis
Dayoub, H., Achan, V., Adimoolam, S., Jacobi, J., Stuehlinger, M. C., Wang, B., Tsao, P. S., Kimoto, M., Vallance, P. J., Patterson, A. J., et al. (2003) · Circulation · doi:10.1161/01.cir.0000101924.04515.2e · Cited by 340
Self-citationArginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta.
Cooke, J. P., Andon, N., Girerd, X. J., Hirsch, A. T., & Creager, M. A. (1991) · Circulation · doi:10.1161/01.cir.83.3.1057 · Cited by 332
Self-citationEnhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine.
Tsao, P. S., McEvoy, L. M., Drexler, H., Butcher, E. C., & Cooke, J. P. (1994) · Circulation · doi:10.1161/01.cir.89.5.2176 · Cited by 324
Self-citationSydow, K., Daiber, A., Oelze, M., Chen, Z., August, M., Wendt, M., Ullrich, V., Mülsch, A., Schulz, E., Keaney, J. F., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419267 · Cited by 300
Clinical Trials for Claudication
Hiatt, W. R., Hirsch, A. T., Regensteiner, J. G., & Brass, E. P. (1995) · Circulation · doi:10.1161/01.cir.92.3.614 · Cited by 290
Böger, R. H., Bode‐Böger, S. M., Thiele, W., Creutzig, A., Alexander, K., & Frölich, J. C. (1998) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(98)00375-1 · Cited by 263
Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay
Schulze, F., Wesemann, R., Schwedhelm, E., Sydow, K., Albsmeier, J., Cooke, J. P., & Böger, R. H. (2004) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2004.257 · Cited by 252
Self-citationThum, T., Tsikas, D., Stein, S., Schultheiß, M., Eigenthaler, M., Anker, S. D., Poole-Wilson, P. A., Ertl, G., & Bauersachs, J. K. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.04.066 · Cited by 234
Erwin, P. A., Lin, A. J., Golan, D. E., & Michel, T. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413058200 · Cited by 215
l -Arginine Induces Nitric Oxide–Dependent Vasodilation in Patients With Critical Limb Ischemia
Bode‐Böger, S. M., Böger, R. H., Alfke, H., Heinzel, D., Tsikas, D., Creutzig, A., Alexander, K., & Frölich, J. C. (1996) · Circulation · doi:10.1161/01.cir.93.1.85 · Cited by 196
Effect of Supplemental Oral l-Arginine on Exercise Capacity in Patients With Stable Angina Pectoris
Ceremuzyński, L., Chamiec, T., & Herbaczyńska-Cedro, K. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(97)00354-8 · Cited by 173
Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis
McVEIGH, G. E., ALLEN, P. B., MORGAN, D. R., HANRATTY, C. G., & SILKE, B. (2001) · Clinical Science · doi:10.1042/cs1000387 · Cited by 144
Mittermayer, F., Krzyżanowska, K., Exner, M., Mlekusch, W., Amighi, J., Sabeti, S., Minar, E., Müller, M. M., Wolzt, M., & Schillinger, M. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000242801.38419.48 · Cited by 143
Jacobi, J., Sydow, K., von Degenfeld, G., Zhang, Y., Dayoub, H., Wang, B., Patterson, A. J., Kimoto, M., Blau, H. M., & Cooke, J. P. (2005) · Circulation · doi:10.1161/01.cir.0000158487.80483.09 · Cited by 143
Self-citationAngiogenesis Is Impaired by Hypercholesterolemia
Jang, J. J., Ho, H. –. V., Kwan, H. H., Fajardo, L. F., & Cooke, J. P. (2000) · Circulation · doi:10.1161/01.cir.102.12.1414 · Cited by 133
Self-citationMaxwell, A. J., Anderson, B. E., & Cooke, J. P. (2000) · Vascular Medicine · doi:10.1177/1358836x0000500103 · Cited by 107
Self-citationDimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease
Tanaka, M., Sydow, K., Gunawan, F., Jacobi, J., Tsao, P. S., Robbins, R. C., & Cooke, J. P. (2005) · Circulation · doi:10.1161/circulationaha.105.537670 · Cited by 103
Self-citationArginine metabolism in vascular biology and disease
Morris, S. M. (2005) · Vascular Medicine · doi:10.1177/1358836x0501000112 · Cited by 85
Randomized trial of a medical food for the dietary management of chronic, stable angina
Maxwell, A. J., Zapien, M. P., Pearce, G., MacCallum, G., & Stone, P. H. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01708-9 · Cited by 73
Wang, B., Candipan, R. C., Arjomandi, M., Hsiun, P. T. C., Tsao, P. S., & Cooke, J. P. (1996) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(96)00337-3 · Cited by 71
Self-citationl -Arginine enhances aerobic exercise capacity in association with augmented nitric oxide production
Maxwell, A. J., Ho, H. –. V., Le, C. Q., Lin, P. S., Bernstein, D., & Cooke, J. P. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.3.933 · Cited by 69
Self-citationBednarz, B., Jaxa-Chamiec, T., Maciejewski, P., Szpajer, M., Janik, K., Gniot, J., Kawka‐Urbanek, T., Drozdowska, D., Gessek, J., & Laskowski, H. (2005) · PubMed · Cited by 64
Comparison of arterial assessments in low and high vascular disease risk groups
Wilson, A. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2003.10.009 · Cited by 63
Self-citationA pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease
Oka, R. K., Szuba, A., Giacomini, J. C., & Cooke, J. P. (2005) · Vascular Medicine · doi:10.1191/1358863x05vm637oa · Cited by 53
Self-citationL-arginine supplementation prolongs exercise capacity in congestive heart failure.
Bednarz, B., Jaxa-Chamiec, T., Gebalska, J., Herbaczyńska-Cedro, K., & Ceremuzyński, L. (2004) · PubMed · Cited by 48
Effects of asymmetric dimethylarginine (ADMA) infusion in humans
Kielstein, J. T., Tsikas, D., & Fliser, D. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0010-1 · Cited by 42
Comparative effects of cilostazol and other therapies for intermittent claudication
Dawson, D. L. (2001) · The American Journal of Cardiology · doi:10.1016/s0002-9149(01)01673-3 · Cited by 41
Bednarz, B., Wolk, R. A., Chamiec, T., Herbaczyńska-Cedro, K., Winek, D., & Ceremuzyński, L. (2000) · International Journal of Cardiology · doi:10.1016/s0167-5273(00)00324-7 · Cited by 34
ADMA regulates angiogenesis: genetic and metabolic evidence
Achan, V., Ho, H. –. V., Heeschen, C., Stuehlinger, M., Jang, J. J., Kimoto, M., Vallance, P. J., & Cooke, J. P. (2005) · Vascular Medicine · doi:10.1191/1358863x05vm580oa · Cited by 29
Self-citationVascular compliance versus flow-mediated vasodilation: correlation with cardiovascular risk factors
Nair, N., Oka, R. K., Waring, L. D., Umoh, E. M., Taylor, C. B., & Cooke, J. P. (2005) · Vascular Medicine · doi:10.1191/1358863x05vm633oa · Cited by 15
Self-citationAsymmetric dimethylarginine (ADMA): an endogenous inhibitor of angiogenesis
Cooke, J. P. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0005-y · Cited by 10
Self-citationADMA, Endothelial Progenitor Cells, and Cardiovascular Risk
Thum, T., & Bauersachs, J. K. (2005) · Circulation Research · doi:10.1161/res.97.8.e84 · Cited by 7
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Metadata
- Authors
- Wilson, A. M., Harada, R., Nair, N., Balasubramanian, N., & Cooke, J. P.
- Affiliations
- Stanford Medicine (US)
- Venue
- Circulation
- Published
- 2007-07-10
- Volume
- 116
- Issue
- 2
- Pages
- 188-195
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2000796869
- Cited by
- 241
- References
- 48
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 4 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 14 · 2019: 9 · 2018: 11 · 2017: 24 · 2016: 15 · 2015: 13 · 2014: 13 · 2013: 12 · 2012: 26
- FWCI
- 16.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Royal Australasian College of Physicians
- National Health and Medical Research Council
- National Medical Research Council
- National Heart, Lung, and Blood Institute (R01 HL-63685, R01HL075774, T32HL007708, R01HL063685, P50HL083800)
- National Institute of Allergy and Infectious Diseases (P01AI050153, P01AI50153)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- arginine supplementation, peripheral arterial disease, intermittent claudication, nitric oxide, endothelial function, flow-mediated dilation, vascular compliance, citrulline, claudication distance, long-term supplementation, placebo effect
- MeSH terms
- Aged, Arginine, Brachial Artery, Female, Humans, Intermittent Claudication, Male, Middle Aged, Placebos, Prospective Studies, Peripheral Vascular Diseases, Patient Selection, Nitric Oxide Synthase, Dietary Supplements, Racial Groups
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